1dx6

STRUCTURE OF ACETYLCHOLINESTERASE COMPLEXED WITH (-)-GALANTHAMINE AT 2.3A RESOLUTION
(see also AChE inhibitors and substrates (Part II))

Biological Context
Alzheimer's disease is a disorder that attacks the central nervous system through progressive degeneration of its neurons. Patients with this disease develop dementia which becomes more severe as the disease progresses. It was suggested that symptoms of Alzheimer's disease are caused by a decrease in the activity of cholinergic neocortical and hippocampal neurons. Treatment for Alzheimer's disease by acetylcholine (ACh) precursors and cholinergic agonists was ineffective or caused side effects. The enzyme acetylcholinesterase (AChE) hydrolyses ACh, resulting in termination of cholinergic neurotransmission. Therefore, compounds which inhibit AChE might significantly increase the levels of ACh depleted by Alzheimer's disease. Galanthamine (GAL; Reminyl) is an AChE inhibitor and it is currently used for palliative therapy of Alzheimer's disease.



Structural Details
Galanthamine (GAL; colored red) is an alkaloid from the flower snowdrop (Galanthus nivalis). The X-ray crystal structure of GAL bound in the active site of TcAChE (1dx6) was determined at 2.3 Å resolution. The inhibitor binds at the base of the active site gorge of TcAChE, interacting with both the choline-binding site (Trp84) and the acyl-binding pocket (Phe288, Phe290). The tertiary amine appears to make a non-conventional hydrogen bond (3.44Å), via its N-methyl group, to Asp72. The hydroxyl group of the inhibitor makes a strong hydrogen bond (2.7 Å) with Glu199. ACh (gray) is shown for comparison.

About this Structure
1DX6 is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.

Additional Resources
For additional information, see: Alzheimer's Disease

Reference
Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution., Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL, FEBS Lett. 1999 Dec 17;463(3):321-6. PMID:10606746

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